Skin disorders due to ultraviolet are attracting attention both from the viewpoint of aesthetics and from the viewpoint of cancer control. Epithelial keratinized cells (keratinocytes), which account for the majority of the epithelium, are observed to have abnormalities in the growth and/or differentiation thereof in various dermatitides that occur as complications in psoriasis, ichthyosis, collagen disease and the like. From this fact, it is thought that controlling the growth and/or differentiation of keratinocytes is extremely important to the health of living organisms.
The skin is an organ configured by the epidermis, which consists of overlain epithelial cells, and the dermis, which consists of dense connective tissue, forming the barrier between the outer environment and the inside of the body. The epidermis is a tissue about 1 mm in thickness that forms the outermost layer of the skin, being in direct contact with the atmosphere and protecting the inside of the skin against various stimuli (for example, solar rays, dryness, dust and the like).
The upper layer of the human skin, which confers elasticity and the barrier characteristic to the skin, that is, the epidermis, consists of four cell types defined by distinct differentiation stages (basal cell layer, which is the border of the junction between the dermis and the epidermis, prickle cell layer, granular layer, and keratinized layer).
Of the cells that constitute the epidermis, 80% are keratinized cells (keratinocytes). Keratinocytes, which have the capability of cell division, are present in the basal cell layer and move to the prickle cell layer, granular layer, and keratinized layer with the progress of differentiation. Terminal cells of the corneal layer, which are called corneocytes, are already dead. The epidermis is a constantly renewed tissue, and the program for cell cleavage and progress to finally differentiated corneocytes is very strictly controlled. In the basal cell layer, cell division occurs constantly; the resulting cells move while changing the shape thereof, and about 28 days later, they drop off from the corneal layer as dirt.
As such, the differentiation of the epidermis, which turns over in a 28-day cycle, is important to the conferment of the essential function of the skin, that is, the conferment of the protective barrier against the outer environment, and the prevention of the loss of water from the body.
The skin is sensitively influenced by temperature/humidity, ultraviolet, cosmetics, aging, disease, stress, dietary habits and the like; as a result, various troubles, including deterioration of the above-described skin functions and skin senescence, occur.
Ultraviolet (UV) has a sterilizing action and has effects of promoting bone formation by vitamin D and improving the immune function of the skin, and on the other hand produces skin thickening, wrinkle or pouch formation, pigmentation and the like.
As acute reactions due to ultraviolet in the skin, sunburns and photosensitive dermatitis can be mentioned; as chronic reactions, skin pigment abnormalities (exacerbation of stains and freckles) and promotion of skin senescence can be mentioned. When the skin is exposed to ultraviolet, an enzyme system of the arachidonic acid cycle is induced in skin cells, resulting in the generation of prostaglandin E2. Prostaglandin E2 has a function to inflame skin cells, causing red swelling (erythema) and sunburns. Sunburns in turn cause stains and thicken epidermal cells. As such, epidermal thickening leads to the onset of skin cancer.
Because epidermal thickening is an abnormal growth of keratinocytes, epidermal thickening can be suppressed by suppressing this growth to promote the differentiation thereof.
As major attempts to prevent or ameliorate troubles that occur in the skin, a method of preventing the dryness of the skin and increasing the moisture retention potential of the skin by applying a synthetic or natural moisturizer, a method of improving blood flow by applying a blood circulation promoter, and the like have been performed.
However, these methods pose various problems in terms of prophylactic and ameliorating effects on various skin troubles, the persistency thereof, drug stability and safety, and the like. Specifically, because these methods are generally to replenish water in the epidermis, particularly in the corneal surface, or to supplement part of moisturizer, the indications and effects thereof are transient so that a permanent amelioration of the skin has been unexpectable.
Hence, there is a demand for the development of a substance having a remarkable suppressive action on epidermal thickening, insufficient keratinization of the skin, lipid metabolism abnormalities and the like.
Generally, the growth or differentiation of cells requires a particular growth factor or differentiation factor. Also, the immune responses exhibited by living organisms to bacterial and/or viral infections, tumors and cytotoxicity are regulated by direct or indirect interactions between immunocompetent cells. Cytokines (for example, interleukins, colony stimulating factors, TNFs (tumor necrosis factors), interferons) have been shown to be involved in the differentiation, growth and immune responses of cells.
Interleukin-18 (IL-18) was identified as a novel protein that induces the production of IFN-γ in immunocompetent cells (see, for example, patent document 1). Currently, IL-18 is known to induce not only the production of interferon-γ, which is an inflammatory cytokine, but also the production of anti-inflammatory cytokines (for example, interleukin-4, interleukin-5, and interleukin-13) (see, for example, non-patent document 1).
IL-18 protein is produced as the 24-kDa inactive form (precursor) and cleaved by caspase-1 into the 18-kDa active form, after which it is released out of the cells (see, for example, non-patent document 4). In cultured cells, the IL-18 precursor is expressed in activated macrophages, cerebral microglia, keratinized cells of the skin, Langerhans' cells, corneal epithelial cells, intestinal epithelial cells, uterine gland cells, osteoblasts and the like (see, for example, non-patent document 5). Also, IL-18 protein is known to increase locally in lesions in Alzheimer's disease, Sjoegren's syndrome, Crohn's disease, osteoarthritis, rheumatic arthritis, contact dermatitis, psoriasis, atherosclerosis, and the like (see, for example, non-patent document 6).
IL-18 receptor consists of the α subunit and the β subunit (see, for example, non-patent document 7), and is classified in the IL-1β receptor/TLR family based on the amino acid sequence thereof (see, for example, non-patent documents 5, 6, and 8). The IL-18 activated form protein is known to elevate NF-κB-dependent transcriptional activity and AP-1-dependent transcriptional activity via the IL-18 receptors (see, for example, non-patent document 5). The latter is known to be involved by JNK and p38 MAPK (see, for example, non-patent document 9). The mRNA of the IL-18 receptor α subunit is expressed in the brain, thymus, uterus, adrenal, liver, pancreas, lung, spleen, skeletal muscle, NK cells, T cells and the like (see, for example, non-patent document 6).
Regarding the relationship between IL-18 and disease, it is known that in schizophrenia, neonatal brain hypoplasia, panic disorder, multiple sclerosis, systemic lupus erythematosus (SLE), allergic asthma, hyperthyroidism, type I diabetes mellitus, liver cirrhosis, renal insufficiency, septicemia, atopic dermatitis, premature amniorrhexis, HIV infection, malaria infection and the like, IL-18 protein in patient serum exhibits high values (see, for example, non-patent document 6), and that in patients with endometriosis in chronic stage, the IL-18 protein concentration in ascitic fluid rises (see, for example, non-patent document 10). According to an analysis using animal models, in models of multiple sclerosis or rheumatic arthritis, IL-18 administration worsens the condition, whereas administration of an anti-IL-18 antibody ameliorates or mitigates the condition (see, for example, non-patent documents 11 and 12). On the other hand, in a model of acute graft-versus-host disease (GVHD), IL-18 administration reduces TNFα production and lowers the mortality rate, whereas administration of an anti-IL-18 antibody increases the mortality rate (see, for example, non-patent document 13).
As stated above, there is no definite relationship between IL-18 and disease. This represents the multi-functionality of IL-18, making it more difficult to understand the functions of IL-18 in living organisms.
Patent document 1: Japanese Patent Unexamined Publication No. HEI-8-27189 (published Jan. 30, 1996)
Non-patent document 1: Kyukyu Igaku, volume 26, pages 1823-1826, December 2002
Non-patent document 2: Journal of Immunology, volume 163, pages 1230-1236, 1999
Non-patent document 3: Anticancer Research, volume 19, pages 4131-4138, 1999
Non-patent document 4: Science, volume 275, pages 206-209, 1997
Non-patent document 5: Annu Rev Immunol., volume 19, pages 423-474, 2001
Non-patent document 6: The Cytokine Handbook, fourth edition (Academic Press), volume 2, pages 709-733, 2002
Non-patent document 7: J. Biol. Chem., volume 272, pages 25737-25742, 1997
Non-patent document 8: Life Sci., volume 68, pages 241-258, 2000
Non-patent document 9: Biochem. Biophys. Res. Commun., volume 296, pages 742-748, 2002
Non-patent document 10: Fertil. Steril., volume 80, pages 889-894, 2003
Non-patent document 11: J. Immunol., volume 161, pages 6368-6374, 1998
Non-patent document 12: J. Clin. Invest., volume 104, pages 1337-1339, 1999
Non-patent document 13: J. Exp. Med., volume 194, pages 1433-1440, 2001